1Division of Endocrinology/Diabetes/Metabolism, Temple University School of Medicine, Philadelphia, PA

2Clinical Research Center, Temple University School of Medicine, Philadelphia, PA

3Department of Surgery, Temple University School of Medicine, Philadelphia, PA

4Department of Surgery, University of Medicine and Dentistry New Jersey, Stratford, NJ

5Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA

Corresponding author: Guenther Boden, bodengh{at}tuhs.temple.edu.

Abstract

Endoplasmic reticulum (ER) stress is increased in obesity and is postulated to be a major contributor to many obesity-related
pathologies. Little is known about what causes ER stress in obese people. Here, we show that insulin upregulated the unfolded
protein response (UPR), an adaptive reaction to ER stress, in vitro in 3T3-L1 adipocytes and in vivo, in subcutaneous (sc)
adipose tissue of nondiabetic subjects, where it increased the UPR dose dependently over the entire physiologic insulin range
(from ∼35 to ∼1,450 pmol/L). The insulin-induced UPR was not due to increased glucose uptake/metabolism and oxidative stress.
It was associated, however, with increased protein synthesis, with accumulation of ubiquitination associated proteins, and
with multiple posttranslational protein modifications (acetylations, methylations, nitrosylations, succinylation, and ubiquitinations),
some of which are potential causes for ER stress. These results reveal a new physiologic role of insulin and provide a putative
mechanism for the development of ER stress in obesity. They may also have clinical and therapeutic implications, e.g., in
diabetic patients treated with high doses of insulin.